Viral mimicry driven by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts during cancer therapy remain unclear. Here, we demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating mitochondrial antiviral signaling (MAVS)-mediated dsRNA sensing in conjunction with the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Activation of cytosolic dsRNA sensing cooperates with double-stranded DNA (dsDNA) sensing to upregulate immune cell migration and antigen-presenting machinery. Tracing of dsRNA-sequences reveals that dsRNA-forming transcripts are predominantly generated from non-exonic regions, particularly in locations proximal to genes exhibiting high chromatin accessibility. Activation of this pathway by pulsed monopolar spindle 1 (MPS1) inhibitor treatment, which potently induces micronuclei formation, upregulates cytoplasmic dsRNA sensing and thus promotes anti-tumor immunity mediated by cytotoxic lymphocyte activation in vivo. Collectively, our findings uncover a mechanism in which dsRNA sensing cooperates with dsDNA sensing to boost immune responses, offering an approach to enhance the efficacy of cancer therapies targeting genomic instability.

中文翻译：

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染色体错误分离诱导的 RNA 感应增强了抗肿瘤免疫力


由内源性双链 RNA （dsRNA） 驱动的病毒模拟刺激先天性和适应性免疫反应。然而，在癌症治疗过程中调节 dsRNA 形成转录本的机制仍不清楚。在这里，我们证明 dsRNA 在微核药理学诱导后在癌细胞中显着积累，刺激线粒体抗病毒信号 （MAVS） 介导的 dsRNA 传感与环状 GMP-AMP 合酶 （cGAS）/干扰素基因刺激剂 （STING） 通路。胞质 dsRNA 感应的激活与双链 DNA （dsDNA） 感应合作，上调免疫细胞迁移和抗原呈递机制。对 dsRNA 序列的追踪表明，dsRNA 形成转录物主要由非外显子区域产生，特别是在表现出高度染色质可及性的基因近端的位置。脉冲单极纺锤体 1 （MPS1） 抑制剂治疗激活该通路，有效诱导微核形成，上调细胞质 dsRNA 感应，从而促进体内细胞毒性淋巴细胞激活 介导的抗肿瘤免疫。总的来说，我们的研究结果揭示了 dsRNA 传感与 dsDNA 传感合作以增强免疫反应的机制，提供了一种提高针对基因组不稳定性的癌症疗法疗效的方法。